Multiple genes, including both major histocompatability genes (H2) and non-H2 genes, play important roles in determining resistance to herpesvirus infections by regulating adaptive and innate immune responses, respectively. Definition of the cells, their interactions, relative contributions and genes involved in resistance is essential for the design of innovative strategies to augment resistance to HSV-1. We present here, evidence for a novel locus that governs resistance to HSV-1. The resistance locus that we have provisionally named Herpes Resistance Locus (Hrl) appears closely linked to the TNF p55 receptor (TNFR1) on murine chromosome 6. Hrl was discovered serendipitously in the course of studies to determine whether TNF signaling through the p55 or p75 (TNFR2) or both receptors, was involved in protection against HSV-l. There are at least two alleles for Hrl in inbred mouse strains, a resistance allele and a susceptibility allele present in C57BL/6 and 129 strains, respectively. We have determined in a N2 backcross that Hrl is inherited as dominant autosomal locus that is solely responsible for resistance in male mice, whereas a second locus termed the Sex Modifier Locus, Sml, functions to augment resistant in female mice. In addition to determining resistance to HSV challenge, we present evidence that Hrl also affects HSV reactivation, possibly through interaction with another gene(s). Future studies of Hrl have the potential to reveal new therapeutic targets for HSV-l infections and new approaches for blocking or reducing clinically important recurrent HSV-1 infections such as herpes stromal keratitis, a leading cause of blindness in developed countries. Moreover, the identification and characterization of both Hrl and Sml has the potential to provide important insights into sex-based differences in immunity. The specific aims of this proposal are therefore (1) to genetically map Hrl at high resolution to a 1 cM interval, (2) to identify a B6-derived bacterial artificial chromosome (BAC) clone that can dominantly transfer resistance to HSV induced mortality when expressed as a transgene in the 129 or other susceptible (e.g. AJJ or DBA/2) strain background and (3), to use bioinformatics tools and other approaches to identify possible candidate genes for Hrl in the rescuing BAC and demonstrate that null mutants of the gene in the C57BL/6 background are susceptible to HSV, thereby confirming the candidate gene as Hrl.